Treatment of severe diseases such as cancer and arthritis is one of the fundamental challenges in medical research and the search for new drug delivery technologies in this area is intense and is of great interest to all major pharmaceutical companies worldwide.
US 2009/0022782 A1 discloses a blood retainable device exhibiting selective degradability in tumor tissue. The reference discloses compounds consisting of a phospholipid moiety linked to a poly(alkylene glycol) via a linker, which is cleavable by means of a matrix metalloprotease.
US 2007/0041904 A1 discloses peptides including A-X-B-C, where C is a cargo moiety (e.g. a contrast agent for diagnostic imaging, a chemotherapeutic drug, or a radiation-sensitizer), the B portion includes basic amino acids, X is a cleavable linker sequence and the A portion includes acidic amino acids. This A-X-B-C type of compound includes both basic- and acidic amino acids within the same molecule covalently linked through the cleavable linker X.
US 2006/0210549 A1 discloses lipopeptides including A-(B)-C, where A is a fatty acid (e.g. stearic acid), B is a photo labile linker and C is a polypeptide which is cleavable by proteases such as gelatinases and collagenases.
WO 93/04673 discloses the use of vinyl ether phospholipids, which readily are hydrolyzed by reactive oxygen species or acid, to obtain triggered release from liposomal formulations.
Jølck et al. (Bioconjugate Chem. (2010) 21, 807-810) discloses an efficient method to synthesize PEGylated lipopeptides with the overall structure A-B-C on solid phase support using Click Chemistry where A is a diacyl fatty acid (e.g. stearic acid, palmitic acid or myristic acid), B is a peptide linker which is cleavable by proteases such as gelatinases and collagenases and C is a polymer such as PEG.
Aguilera et al. (Integr. Biol. (2009) 1, 371-381) disclose the in vivo tissue distribution of protease cleavable peptides A-X-B-C where the A portion includes acidic amino acids, the B portion includes basic amino acids, X is a cleavable linker sequence and C is a fluorescent probe. Both basic- and acidic amino acids are combined in the same molecule covalently linked through the cleavable linker X.
Olson et al. (Integr. Biol. (2009) 1, 382-393) disclose the in vivo tumor uptake and the mechanism of activation of protease cleavable peptides A-X-B-C where the A portion includes acidic amino acids, the B portion includes basic amino acids, X is a cleavable linker sequence and C is a fluorescent probe. Both basic- and acidic amino acids are combined in the same molecule covalently linked through the cleavable linker X.
Mignet et al. (Int. J. Pharmaceutics (2008) 361, 194-201) disclose anionic pH-sensitive PEGylated lipoplexes to deliver DNA to tumors.
Hatakeyama et al. (Gene Therapy (2007) 14, 68-77) disclose a systemic gene delivery system for cancer therapy with a tumor-specific cleavable PEG-lipid.
Terada et al. (J. Controlled Release 111 (2006) 333-342) disclose a study of PEG-matrix metalloprotease-2 cleavable peptide-lipid containing galactosylated liposomes for hepatocellular carcinoma-selective targeting.
Zhang et al. (Bioconjugate Chem. 2011, 22, 690-699) disclose amphiphile for DNA delivery.
Mok et al. (Bioconjugate Chem. 2008, 19, 797-801) disclose poly(L-lysine) grafted with multiple biotin-PEG chains.
Gu et al. (Biomacromolecules 2008, 9, 255-262) disclose amphiphile polycations.
Takae et al. (J. Am. Chem. Soc. 2008, 130, 6001-6009) disclose disulfide-linked block catiomers.
Pak et al. (Biochimica et Biophysica Acta 1419 (1999) 111-126) discloses activation of liposomes for delivery.
WO 2006/125134 A1 discloses peptides of the generic structure A-X-B-C where A includes acidic amino acids, X is a cleavable linker, B includes basic amino acids, and C is a cargo moiety.
The present invention offers a solution to one of the fundamental problems in developing nanoparticle-based drug delivery systems for intravenous administration of drugs, which is the route of choice in cancer treatment, i.e. to activate drug release specifically at or in the diseased tissue while maintaining high stability during blood circulation.